"One special advantage of the skeptical attitude of mind is that a man is never vexed to find that after all he has been in the wrong"
Sir William Osler
Well, it's almost Christmas. I know it's Christmas because the animal skeleton situated in the reception of my University's Anatomy School has finally been re-united with his (or her?) Christmas hat, has baubles for eyes and tinsel on its ribcage. This doesn't help with my trying to identify it (oh the irony if it is indeed a reindeer). This term has probably been one of the toughest academic terms I've had, but then when you intercalate that is sort of what you choose to let yourself in for.
I used to think that regular readings were a chore in the pre-clinical years. I had ample amounts of ethics, sociology and epidemiology readings to do but this is nothing compared to the world of scientific papers. The first paper I had to read this term related to Glycosaminoglycan (GAG) integrity in articular cartilage and its possible role in the pathogenesis of Osteoarthritis. Well, I know that now. When I first started reading it felt very much like a game of boggle and highly reminiscent of high school spanish lessons where I just sat and nodded my head. This wasn't the end. Every seminar has come with its own prescribed reading list. The typical dose is around 4-5 papers.
This got me thinking. We don't really spend all that much time understanding how to read scientific papers nor do we really explore our roles as 'scientists' as well as future clinicians. Training programmes inevitably seem to create false divides between the 'clinicans' and the 'academics' and sometimes this has negative consequences - one simply criticises the other: Doctors don't know enough about science, academics are out of touch with the real world etc...
Doctors as scientists...
The origins of medicine itself lie with some of the greatest scientists of all time - Herophilus, Galen, Da Vinci, William Harvey (the list is endless). As well as being physicians, all of these people were also respected scientists who regularly made contributions to our understanding of the body's mechanics. Albeit, the concept of ethics was somewhat thrown to the wind (Herophilus, though dead for thousands of years, is regularly accused of performing vivisections on prisoners in his discovery of the duodenum).
Original sketches by William Harvey which proved a continuous circuit of blood being supplied and leaving the upper limb. He used his observations to explain the circulatory system as we know it today
What was unique about these people? The ability to challenge what they saw. They made observations, tested them against their own knowledge and asked more questions - they wanted to know more. As well as being doctors, we have the unique opportunity to make observations and question what we see. What's causing x to turn into y? What trends do we see in patients presenting with x? The most simple question can lead to the biggest shift in understanding. It only took Semmelweiss to ask why women were dying in a maternity ward to give rise to our concept of modern infection control.
Bad Science...
Anyone who has read the ranting tweets, ranting books and ranting YouTube TED videos of academic/GP Ben Goldacre will be familiar with this somewhat over used term. Pseudoscience (coined by the late great Karl Popper) is a much more sensible and meaningful term. Science is about gathering evidence which supports your hypothesis. Pseudoscience is a field which makes claims that cannot be tested by a study.
In truth, there's lots and lots of relatively useless information in print. It's fine knowing about biomarker/receptor/cytokine/antibody/gene/transcription factor (insert meaningless acronym here) but how is it relevant and how does it fit into the bigger picture? Science has become reductionist. We're at the gene level and new reducing levels of study (pharmacogenetics) break this down even further and sometimes, this is at an expense of providing anything useful to your clinicial toolbox.
Increasing job competition and post-graduate 'scoring' systems has also meant there's lots of rushed research in order to get publications and citations. This runs the danger of further undermining the doctors role as a true contributor to science.
Most of it is wrong...
I read an article recently that told me at least 50% of what I learn in medical school will be proven wrong in my lifetime. That might seem disheartening since I may have pointlessly consumed ample coffee to revise erroneous material. However, it's also exciting. What if you prove it wrong? What if you contributed to changing our understanding? As a doctor, there's no reason why you can't.
If we're going to practice evidence-based medicine then we need to understand that evidence and doing this requires us to wear our scientist hat. It would be nice to see a whole generation of doctors not just willing to accept our understanding but to challenge that which is tentative. That's what science is all about.
Here's hoping you don't find any meta-analyses in your stockings.
Merry Christmas.

It was a Saturday, about tea-time in the quaint village of Athelstaneford, East Lothian. Mrs Alexandria Agutter sat in her cottage, enjoying the delights of the late-summer evening with a glass of gin and tonic. She listlessly sipped from the rather generous pick-me up, no doubt chewing over the happenings of the day. Blast! The taste was much too bitter to her liking. She stood up. And promptly crumpled to the floor in a dizzied heap. It had not been five minutes when a fiery pain gripped her parched throat and in her frenzied turn she watched the bleary room become draped in a gossamery silk.
How Dame Agatha would approve. But this is no crime novel, on that fateful day, 24th August 1994, poor Mrs Agutter immortalised herself in the history books of forensic medicine; she was the victim of a revered toxin and a vintage one it was too. She had unwittingly imbibed a G&T laced with a classic poison of antiquity.
A clue from the 21st century: do you recall the first Hunger Games film adaption? Those inviting purple-black berries or as Suzanne Collins coined them ‘Nightlock’; a portmanteau of hemlock and Deadly Nightshade. True to the laters’ real life appearance those onscreen fictional fruits played a recurring cameo role.
Deadly Nightshade is a perennial shrub of the family Solanaceae and a relative of the humble potato (a member of the Solanus genus). It is a resident of our native woodland and may be found as far afield as Europe, Africa and Western Asia. The 18th century taxonomist, Carl Linnaeus gave the plant an intriguing name in his great Species Plantarum. The genus Atropa is aptly named after one of the three Greek Fates, Atropos. She is portrayed shearing the thread of a mortal’s life so determining the time and manner of its inevitable end. The Italian species name belladona (beautiful woman) refers to the striking mydriatic effect of the plant on the eye. The name pays homage to Pietro Andre Mattioli, a 16th century physician from Sienna, who was allegedly the first to describe the plant’s use among the Venetian glitterati - ladies of fashion favoured the seductive, doe-eyed look. Belladona is poisonous in its entirety. It was from the plant’s roots in 1831, the German apothecary Heinrich F. G. Mein isolated a white, odourless, crystalline powder: it was (surprise, surprise) atropine.
Atropine is a chiral molecule. From its natural plant source it exists as a single stereoisomer L-atropine, which also happens to display a chiral potency 50-100 times that of its D-enantiomer. As with many other anaesthetic agents it is administered as a racemic mixture. How strange that atropine now sits among the anaesthetist’s armamentarium, its action as a competitive antimuscarinic to counter vagal stimulation belies its dark history. It was a favourite of Roman housewives seeking retribution against their less than faithful husbands and a staple of the witch’s potion cupboard. Little wonder how belladona became known as the Devil’s plant. Curiouser still it’s also the antidote for other poisons, most notably the organophosphates or nerve gases.
On account of its non-selective antagonism, atropine produces a constellation of effects: the inhibition of salivary, lacrimal and sweat glands occurs at low doses; dry mouth and skin are early markers. Pyrexia is a central effect exacerbated by the inability to sweat. Flushing of the face due to skin vessel vasodilatation. Low parasympathetic tone causes a moderate sinus tachycardia. Vision is blurred as the eye becomes dilated, unresponsive to light and accommodation is impaired. Mental disorientation, agitation and ataxia give the impression of drunkedness or a delirium tremens like syndrome. Visual hallucinations, often of butterflies or silk blowing in the wind, are a late feature.
It was then that Mr Agutter, seemingly untroubled by the sight of his wife’s problematic situation, proceeded to leave a message with the local practitioner. How fortunate they were to have the vigilant locum check the answering machine and come round to the Agutter’s lodge accompanied by an ambulance crew. The attending paramedic had the presence of mind to pour the remainder of Mrs Agutter’s beverage into a nearby jam jar, while Mr Agutter handed over what he suspected to be the offending ingredient: the bottle of Indian tonic water. As it soon transpired there were seven other casualties in the surrounding countryside of East Lothian – all involving an encounter with tonic water.
In fact by some ironic twist of fate, two of the victims were the wife and son of Dr Geoffry Sharwood-Smith, a consultant aneasthetist. Obviously very familiar with the typical toxidrome of anticholinergic agents, he was quick to suspect atropine poisoning. Although for a man of his position with daily access to a sweetshop of drugs, it was not something to draw attention to.
Through no small amount of cunning had the poisoner(s) devised the plan. It was elegant; atropine is very bitter. So much so that it can be detected at concentrations of 100 parts per million (0.001%). Those foolish enough to try the berries of belladonna during walks in the woods are often saved by the berry’s sour taste. They are soon spat out. But the quinine in the tonic water was a worthy disguise. The lethal dose for an adult is approximately 90-130mg, however atropine sensitivity is highy variable. In its salt form, atropine sulfate, it is many times more soluble: >100g can be dissolved in 100ml of water. So 1ml may contain roughly tenfold the lethal dose.
There ensued a nationwide scare; 50 000 bottles of Safeway branded Indian tonic water were sacrificed. Only six bottles had been contaminated. They had all been purchased, tops unsealed, from the local Safeway in Hunter’s Tryst. Superficially this looked like the handiwork of a psychopath with a certain distaste for the supermarket brand, and amidst the media furore, it did have some verisimilitude: one of the local papers received a letter from 25 year old, Wayne Smith admitting himself as the sole perpetrator.
The forensic scientist, Dr Howard Oakley analysed the contents of the bottles. They all contained a non-lethal dose, 11-74mg/litre of atropine except for the Agutter’s, it contained 103mg/litre. The jam jar holding Mrs Agutter’s drink bore even more sinister results, the atropine concentration was 292mg/L. It would appear Mrs Agutter had in some way outstayed her welcome. But she lived. A miscalculation on the part of the person who had added an extra seasoning of atropine to her drink. According to the numbers she would have had to swallow a can’s worth (330ml) to reach the lethal dose. Thankfully she had taken no more than 50mg.
The spotlight suddenly fell on Dr Paul Agutter. He was a lecturer of biochemistry at the nearby University of Napier, which housed a research syndicate specialising in toxicology. CCTV footage had revealed his presence at the Safeway in Hunter’s Tryst and there was eye witness evidence of him having placed bottles onto the shelves. Atropine was also detected by the forensic investigators on a cassete case in his car. Within a matter of two weeks he would be arrested for the attempted murder of his wife. Despite the calculated scheme to delay emergency services and to pass the blame onto a non-existent mass poisoner, he had not accomplished the perfect murder. Was there a motive? Allegedly his best laid plans were for the sake of a mistress, a mature student from Napier. He served seven years of a twelve year sentence. Astonishingly, upon his release from Glenochil prison in 2002, he contacted his then former wife proclaiming his innocence and desire to rejoin her in their Scottish home. A proposition she was not very keen on. Dr Agutter was employed by Manchester University as a lecturer of philosophy and medical ethics. He is currently an associate editor of the online journal Theoretical Biology and Medical Modelling.
We will never know the true modus operandi as Dr Agutter never confessed to the crime. Perhaps all this story can afford is weak recompense for the brave followers of the Dry January Campaign. Oddly these sort of incidents never appear in their motivational testimonials.
Acknowledgements
Emsley J. Molecules of Murder. 2008, Cambridge, RSC Publishing, p.46-67.
Lee MR. Solanaceae IV: Atropa belladona, deadly nightshade. J R Coll Physicians Edinb. March 2007; 37: 77-84.
Illustrator Edward Wong
This blog post is a reproduction of an article published in the The Medical Student Newspaper January issue, 2014
http://www.themedicalstudent.co.uk/

In September 2014 it emerged that a group of scientists at the Karolinska Institute in Sweden had been sneaking the lyrics of Bob Dylan into their papers as part of a long running bet. The story, originally published in the house magazine KI-Bladet, quickly went viral—spreading from the local Swedish press to international media such as the Guardian and Washington Post.1 2 It all started in 1997 with a review in Nature Medicine entitled “Nitric oxide and inflammation: the answer is blowing in the wind.”3 A local phenomenon was thus revealed, but was this Dylan citing unique to the Karolinska Institute? We decided to investigate how Dylan’s lyrics are cited in the biomedical literature.

A 40 year old woman presented to the surgical assessment unit with a 12 hour history of abdominal distension and tenderness. She had not opened her bowels or passed wind since her symptoms started. An abdominal radiograph was requested—what does it show (fig 1)?